Morpholine-mediated defluorinative cycloaddition of gem-difluoroalkenes and organic azides

Here, we report the first transition-metal-free defluorinative cycloaddition of gem-difluoroalkenes with organic azides in morpholine as a solvent to construct fully decorated morpholine-substituted 1,2,3-triazoles. Mechanistic studies revealed the formation of an addition–elimination intermediate of morpholine and gem-difluoroalkenes prior to the triazolization reaction via two plausible pathways. Attractive elements include the regioselective and straightforward direct synthesis of fully substituted 1,2,3-triazoles, which are otherwise difficult to access, from readily available starting materials.


General information
Unless otherwise noted, all reactions were carried out under argon atmosphere.All commercially available reagents were used without further purification.All of the solvents were treated according to known methods.For TLC, Sorbtech silica XG TLC plates w/UV254 indicator was used and visualized under a UV lamp.Flash column chromatography was performed in Biotage Isolera One with Biotage SNAP 10-50g cartridges. 1 H, 19 F, and 13 C NMR spectra were recorded on a Bruker Avance-500 (125 MHz) spectrometer and chemical shifts are reported in ppm (δ) using deuterated solvents for 1 H, 13 C NMR, and 19 F NMR. CDCl 3 (δ = 77.16ppm) for 13 C NMR, CFCl 3 (δ = 0 ppm) for 19 F NMR, and CDCl 3 (δ = 7.26 ppm) for 1 H NMR were used as internal standards.HRMS was recorded using quadruple-TOF was used to obtain the data both in positive and negative modes.ATR-IR was taken using an Agilent Technologies Cary 600series FTIR Spectrometer.Melting point was recorded using the Stanford Research System OptiMelt Automated Melting Point System.Data were reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, td = triplet of doublets, qd = quartet of doublets, h = m = multiplet), coupling constants (Hz) and integration.LiHMDS was acquired from Thermo Scientific Chemicals in a 100 mL glass container, appropriately labeled as lithium bis(trimethylsilyl)amide, 1 M solution in THF/ethylbenzene, AcroSeal™, Thermo Scientific Chemicals.Its corresponding catalog number: 347701000.

Azides safety
Caution must always be exercised when working with azides.It is important to ensure that the carbon-to-nitrogen ratio in organic azides remains above three.An alternative guideline known as the "rule of six" dictates that there should be a minimum of six carbon atoms per energetic functional group.Organic azides, especially those with low molecular weight or high nitrogen content, have the potential to be explosive.The application of heat, light, or pressure can trigger the decomposition of azides.Additionally, the azide ion is toxic, necessitating the use of gloves when handling sodium azide.When conducting experiments involving heating azides in the presence of copper, a blast shield should always be employed.It is crucial to never mix azides or their waste with acidic, metallic, or halogenated solvents.
[b] 2.0 Equiv of azide was used. [c] 0.1 Equiv of catalyst used unless otherwise noted. [d] Isolated yield. [e] para-Fluorophenyl azide was used for screening to facilitate reaction monitoring via 19 F NMR. Yield was obtained by utilizing the relative integration.
[e] The yield was obtained by utilizing the relative integration

General procedure for synthesizing gem-difluoro olefins
In an oven-dried, Ar-flushed vial charged with a stirring bar, sodium 2-chloro-2,2-difluoroacetate (6.0 mmol, 1.5 equiv) and triphenylphosphine (5.0 mmol, 1.2 equiv) were added.The vial was then vacuumed and flushed with Ar three times.Next, DMF (1.20 mL, 1.5 mL/mmol) was added and stirred until the reaction mixture became homogenous.Once mixed, the appropriate aldehyde (0.8 mmol, 1 equiv) was added and stirred at 100 °C under Ar.Caution when using balloons due to carbon dioxide evolution.The reaction mixture was stirred for 6 h or until completion (monitored by TLC or 19 F NMR spectroscopy) under the same conditions.Spectroscopic data for (1c) are consistent with previously reported data for this compound [3].

General procedure for the synthesis of organic azides
Method A: The corresponding aniline (500 mg, 1 equiv) was suspended in methanol (4 mL) and water (3 ml).Then, HCl (2 mL) was added at 0 °C to the mixture which was stirred for another 5 minutes.The mixture was stirred at 0 °C for 20 minutes after which sodium nitrite (1.2 equiv) in water (1.5 mL) was added dropwise over 10 minutes.After a solution of sodium azide (1.2 equiv) in water (1.5 mL) was added dropwise to the reaction mixture for over 10 minutes, the reaction mixture was stirred at room temperature for 2 h or until completion (monitored by TLC) under the same conditions.The reaction was quenched with water and the organic layer was extracted with ethyl acetate (× 3), dried with anhydrous Na 2 SO 4 , and concentrated using a rotavap.Unless other noted, the organic azides were used without further purification.
Warning: Working with azides demands caution due to potential explosiveness.This reaction can form hydrazoic acid which is highly explosive.Guidelines include a carbon-to-nitrogen ratio above three and the "rule of six," requiring six carbon atoms per energetic group.High-nitrogen organic azides are sensitive to heat, light, and pressure, possibly exploding.Sodium azide, with toxic azide ions, needs glove use.Copper-heated azides require a blast shield.Avoid mixing azides or waste with acidic, metallic, or halogenated solvents for safety.For more information, please see the warning on page 2 of the SI.

Method B:
The corresponding aniline (500 mg, 1 equiv) and sodium azide (1.2 equiv) were suspended in DMF (2 mL, 1 M) and the reaction mixture was stirred at 60 °C for 6 h or until completion (monitored by TLC).The reaction was quenched with brine and the organic layer was extracted with ethyl acetate (× 3), dried with anhydrous Na 2 SO 4 , and concentrated in vacuo.The products were obtained after purification by column chromatography (gradient: 0-20% ethyl acetate in hexane) on silica gel.

Time course study
In an oven-dried, Ar-flushed vial with a stirring bar, a solution of 1-(2,2-difluorovinyl)-4methylbenzene (1, 30 mg, 1 equiv) and 4-azidobenzonitrile (2b, 42 mg, 1.5 equiv) were dissolved in morpholine (0.3 mL, 0.4 M).The solution was stirred for 10 minutes at room temperature under Ar.Then, LiHMDS (78 µL, 1 M in THF, 0.4 equiv) was added to the reaction mixture and it was purged with Ar three times.The reaction mixture was subjected to continuous stirring at a temperature of 75 °C.After 30 min, 1 h, 2 h, 4 h, 8 h, 16 h, 24 h, 32 h, and 48 h, 50 µL aliquots of the reaction mixture were withdrawn using a syringe.The progress of the reaction was monitored by 19 F NMR (Figure 3 in main text).

Table S2 :
Difference between the calculated and the observed HRMS data.